rs1554821022

chr9-132928830-CCAGCATGGCAAGAAGCTCC-CTTG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000368.5(TSC1):c.24_42delinsCAA(p.Glu9LysfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G8G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC1 NM_000368.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.94

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 811 pathogenic variants in the truncated region.
• PP5: Variant 9-132928831-CAGCATGGCAAGAAGCTCC-TTG is Pathogenic according to our data. Variant chr9-132928831-CAGCATGGCAAGAAGCTCC-TTG is described in ClinVar as [Pathogenic]. Clinvar id is 466078.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.24_42delinsCAA	p.Glu9LysfsTer12	frameshift_variant	3/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.24_42delinsCAA	p.Glu9LysfsTer12	frameshift_variant	3/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2018

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant has not been reported in the literature in individuals with a TSC1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu9Lysfs*12) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554821022; hg19: chr9-135804218;